**2. Epidemiology of lupus nephritis**

SLE is a disease with a prevalence ranging between 30 and 50 cases per 100,000 people worldwide [12]. In the USA, the incidence of SLE is estimated between 5.5 and 7.4 cases per 100,000 persons-years [13]. In Europe, where there are discrepancies between different national SLE registries, the estimated incidence of SLE varies between 1.5 and 7.4 per 100,000 persons-years [14]. In South America, the incidence varies between 1 and 4.2 cases per 100,000 persons-years [14], while in Asia, incidence ranges between 2.8 and 8.6 cases per 100,000 persons-years; in Australasia, there are at least 11 cases per 100,000 persons-years [14]. These data showcase that the prevalence and incidence of lupus in a population is related to the ethnicity of the population. In the USA, it was shown [13] that SLE is commoner in African American, then in Hispanics, and is less common in Caucasian. It is widely known that 90% of patients with SLE are women [12]. In this regard, gender and ethnicity impact the incidence and prevalence of SLE.

The frequency of LN varies between different regions of the world and different ethnicities. Overall, 30–60% of patients with lupus and 70% of children with SLE develop LN [15]. It has been shown that LN is more frequent in the Black population with SLE than in Asians and Hispanic populations and less common in Caucasians [16]. The difference in frequency can be attributed to "high-risk" genotypes. For instance, a significant association between the known "high-risk" APOL1 alleles and LN has been shown [17]. These alleles can be found in Black patients, explaining the higher prevalence of LN in these patients. LN has a significantly higher frequency in male patients with SLE when compared to females [18–20]. Furthermore, LN is more common in patients with childhood onset lupus when compared with adult-onset lupus [21].

#### **3. Pathogenesis of lupus nephritis**

The pathogenesis of LN is complex with distinct factors (genetic, hormonal, and environmental) influencing the natural course of the disease [22]. The bottom line of LN pathogenesis is the production of autoantibodies against autoantigens, with double-stranded DNA being the commonest target [23]. There are two ways that anti-ds DNA antibodies exert their nephritogenic effect. First, immune complexes are formed in the circulation that are deposited to the glomeruli. Second, anti-ds DNA antibodies

#### *Lupus Nephritis: Clinical Picture, Histopathological Diagnosis, and Management DOI: http://dx.doi.org/10.5772/intechopen.109498*

are connected to the glomeruli *in situ* either by binding to exposed chromatin fragments connected to glomerular membranes and mesangial matrices or by binding to non-DNA structures connected to the glomerulus that cross-react with anti-ds DNA antibodies [22, 23]. All these models are required for the fragments of chromatin to be exposed for anti-ds DNA antibodies to be produced. Seredkina et al. [24] showed that this chromatin exposure is achieved in mice because of renal DNAse1 deficiency, leading to reduced clearance of apoptotic material. The surplus apoptotic material led to a surge of anti-ds DNA levels and the formation of mesangial immune deposits [25]. Reduced levels of renal DNAse1 have been observed in humans with LN as well [25]. It must be noted that not all anti-ds DNA antibodies are nephritogenic [26]; only a subset is able to get deposited in the kidney. It has been shown that autoantibodies against annexin-a2 [27] and autoantibodies against moesin [28], antigens found in the glomeruli, cause proliferative LN. At the same time, patients with membranous LN present with immune complexes consisted by exostosin-1/exostosin-2 antigens and autoantibodies [29] and immune complexes with neural cell adhesion molecule 1 [30]. It can be assumed that this great heterogeneity in SLE autoantibodies is the reason behind the different classes of LN.

The surplus apoptotic material described before activates dendritic cells, monocytes, and macrophages [22]. These cells, through the production of cytokines and the presentation of autoantigens, activate effector B cells by prolonging their survival and maturation process. This way, the number of autoreactive B cells, memory cells, plasma cells, and produced autoantibodies is increased [22]. Recently, a new function of B cells has been discovered. Besides their function as antibody-producing cells, B cells seem to aggregate in inflamed organs creating complex structures that are called tertiary lymphoid tissue [31]. This tissue form ranges from small clusters of lymphocytes to sophisticated structures reminiscent of lymph nodes. This tissue is observed on kidneys in a variety of different diseases from chronic pyelonephritis to autoimmune disease. Their role is to produce *in situ* autoantibodies and proinflammatory cytokines, activate T cells, and cause lymph angiogenesis [32]. Shen et al. [33] showed that intrarenal B cell infiltrates were found in 60% of patients with LN and were associated with LN class IV, greater activity and chronicity indices, and worse glomerular filtration rate (GFR). It can be deduced that B cell infiltrates in patients with LN are related to worse outcome.

Besides the proliferation of autoantibody-producing B cells, the surplus apoptotic material triggers innate immunity [8]. The surplus apoptotic material leads to the formation of neutrophil extracellular traps (NETosis) by neutrophils [34]. NETosis is a sequence of cellular events leading to the programmed death of neutrophils and the production of these "traps" (NETs). NETs are web-like DNA structures decorated with histones and cytotoxic proteins, and their role is to trap and destroy pathogens [35]. In sterile conditions, NETs, through their functions, can exacerbate inflammation. First, NETs are a potential source of autoantigens leading to the production of autoantibodies and the formation of immune complexes. Second, NETs serve as a platform for complement activation that leads to inflammation exacerbation and cellular damage. Third, NETs themselves contribute to kidney tissue damage by acting directly on kidney cells, creating microthrombi and releasing cytokines [36].

A critical step in the pathogenesis of LN is the activation of type I interferon system. It has been shown that NETs activate monocytes to produce cytokines such as interferon alpha [37]. However, most of the cytokines are produced by the plasmacytoid dendritic cells [38]. In lupus patients, these cells migrate to tissues (like renal

tissue) [38]. Then, immune complexes containing nucleic acids are internalized, reach the endosome, and stimulate the production of interferon alpha [39]. Under normal circumstances, type I interferons connect to type I interferon receptors that activate other pattern recognition receptors (like toll-like receptors 7 and 9). This cascade of events leads to the expression and stimulation of certain genes and their corresponding enzymes [38]. Some of the enzymes induced lead to the inhibition of viral reproduction [40] highlighting the role of the interferon system in antiviral immunity. At the same time, type I interferon enhances the cytotoxic abilities of natural killer (NK) cells and stimulates the maturation of dendritic cells to antigen-presenting cells [38]. In lupus patients, the overexpression of type I interferon leads to the overexpression of toll-like receptor 7. It has been shown in mice that this overexpression is related to clinically severe SLE [41]. Likewise, it has been shown that patients with nephritis present with an interferon signature and greater levels of interferon I [38].

Complement activation also plays a key role in LN pathogenesis. As already revealed, the first step in LN pathogenesis is the existence of surplus apoptotic material. Under normal circumstances, complement promotes apoptotic debris removal [42]. In patients with SLE, this complement's function is performed in a reduced rate. It has been found that many patients who develop LN present with anti-C1q antibodies [42]. These antibodies further reduce complement's capability of apoptotic debris removal and seem to induce a loop of activation of the classical pathway of complement. Then, the autoantibody mediated renal damage in LN seems to activate the complement via the classical and alternate pathway [43]. Moreover, complement factors like C3a and C5a attract neutrophils and potentiate their response (**Table 1**) [44].
